Our long-term goal is to study the protein ubiquitination pathway in immune regulation. We initiated a new study of the deubiquitinating enzyme CYLD in Tregs by using CYLD floxed Foxp3-cre mice, We found that deficiency of CYLD in Tregs caused chronic lung inflammation. A preliminary study showed that those mutant Tregs expressed altered patterns of chemokine receptors and increased IL-4 production. These preliminary studies pointed to new mechanisms of CYLD regulation of Tregs, via modulating their homing/migration and cytokine production, and they highlight potential tissue-specific aspects of Treg function. These preliminary studies thus provide us with a solid basis for testing our central hypothesis that the ubiquitination/deubiquitination system plays a critical role in the regulation of immune via modulating the homing and/or function of Tregs to particular tissues. Here we plan to test this hypothesis by proposing three Specific Aims: Aim 1, to study CYLD in Treg regulation in the lung; and Aim 2, to study the mechanistic regulation of CYLD-/- Tregs. The expected results will significantly advance our basic knowledge on the context-dependent regulation of Tregs by the protein deubiquitination pathway, and will provide clues to therapeutic intervention of human diseases by harnessing Tregs.